A main goal of SloWave, Inc. is to develop a novel class of sleep-enhancing compounds that, unlike all currently available hypnotics, stimulate slow-wave sleep (SWS), the deepest and most restorative stage of sleep. SloWave plans to develop structural analogs of a natural neuromodulator, gamma-hydroxybutyrate (GHB), which is a potent stimulant of SWS, and has a specific newly identified receptor system in the brain. The objective of this Phase II proposal is to synthesize and screen compounds with the most potent effects on SWS. The specific aims are: 1. To test about 50 GHB agonists, identified by binding assays to have affinity for the GHB receptor, for their ability to induce changes in locomotor activity and body temperature, and to later test about 10 of the lead compounds for their effects on EEG sleep-wake states. 2. To test important hypotheses concerning the mechanisms of action of GHB by examining the effects of various GABAergic or dopaminergic antagonists on GHB-induced alterations in behavioral or physiological state. 3. To determine the effect of chronic treatment with GHB on sleep, and to determine if withdrawal from chronic drug exposure leads to sleep disturbances. The completion of these studies will result in: 1. The identification of 2-3 novel compounds that will subsequently be tested for toxicity prior to human Phase I studies. 2. Increased understanding of the mechanisms of action of GHB on sleep information, which is critical for the design of clinical studies. 3. The definition of the effects of chronic GHB treatment on sleep information, which is important for later pre-clinical studies on the chronic effects of our compounds. The development of GHB related compounds will represent a major breakthrough in the treatment of conditions which involve decreased or abnormal slow-wave sleep, such as aging depression, fibromyalgia and narcolepsy, which together affects many millions of individuals. PROPOSED COMMERCIAL APPLICATION: SloWave will develop a novel class of sleep-enhancing compounds acting via the GHB system which, unlike currently available hypnotics, stimulate slow-wave sleep, the deepest and most restorative stage of sleep, and have a pharmacokinetic profile consistent with the maintenance of sleep and a heightened level of alertness upon awakening. These new compounds will represent a major breakthrough in the treatment of conditions and illnesses which involve disturbed sleep.